Liver damage, types

Renzulin (Approved Dec 1996) Type II Diabetes Liver Damage... 

PXR has been demonstrated to act as an LCA sensor and plays an essential role in detoxification of cholestatic bile acids [11,61]. Studies in different animal models showed that activation of PXR protected against severe liver damage induced by LCA. Pretreatment of wild-type mice, but not the PXR-null mice, with PCN reduced the toxic effects of LCA. Moreover, genetic activation of PXR by expressing the activated... 

Other effects reported in tetryl workers are irritability, fatigue, malaise, headache, lassitude, insomnia, nausea, and vomiting. Anemia, of either the marrow depression or deficiency type, has been observed among tetryl workers. Conjunctivitis may be caused by rubbing the eyes with contaminated hands or by airborne dust keratitis and iridocyclitis have occurred. Tetryl has been reported to cause irreversible liver damage and death after chronic heavy exposure." However, complicat-... 

Chemical injuries to the liver depend on the type of toxic agent, the severity of intoxication, and the type of exposure, whether acute or chronic. The six basic types of liver damage are fatty liver, necrois, hepatobiliary dysfuntions, viral-hke hepatitis, and (on chronic exposure) cirrhosis and neoplasia. A number of organic chemicals and drugs induce fatty liver and hver necrosis. 

The various types of liver damage, which may be caused by toxic compounds, are discussed in the following sections. 

By measurement of the blood level of paracetamol in overdose cases, it is possible to estimate the likely outcome of the poisoning, and hence determine the type of treatment. Measurement of the blood level of paracetamol and its various metabolites at various times after the overdose showed that the half-life was increased several folds (Table 7.3), and the patients who sustained liver damage had an impaired ability to metabolize paracetamol to conjugates (Fig. 7.16). 

Halothane is a very widely used anesthetic drug, which may cause hepatic damage in some patients. It seems that there are two types of hepatic damage, however. One is a very rare reaction, idiosyncratic, resulting in serious liver damage with an incidence of about 1 in 35,000. The other form of hepatotoxicity is a mild liver dysfunction, which is more common and occurs in as many as 20% of patients receiving the drug. The two different types probably involve different mechanisms. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Comparable reports have prompted a questionnaire investigation of 770 patients with type 2 diabetes at the start of acarbose therapy (62). Patients with one or more susceptibility factors for liver damage underwent ultrasonography and autoantibody assays. There was silent liver disease in 13% and 20 patients had a fatty liver without hepatic disease. In 15% of these patients there were slight reversible changes in transaminase activity after acarbose. 

Soriano, M.E., Nicolosi, L., and Bernardi, P., 2004, Desensitization of the permeability transition pore by cyclosporin A prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha, J. Biol. Chem. 279, pp. 36803-36808 Sparagna, G.C., Gunter, K. K., Sheu, S. S., and Gunter, T. E., 1995, Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode, J. Biol. Chem. 270, pp. 27510-27515... 

Since most codeine is dispensed as part of a compound preparation, potential side effects of the other drug(s) must also be considered. For instance, someone with stomach ulcers should not take codeine that is combined with a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Another type of risk from a compound preparation relates to codeine abuse. For instance, a person who abuses codeine might routinely take a dose of 100-200 mg of codeine to produce noticeable euphoria. Using Tylenol 3 to obtain this dose would also mean ingesting 1,000-2,000 mg of acetaminophen. Taking that amount of acetaminophen for any extended period presents a risk for liver damage, especially in combination with alcohol. 

Troglitazone, the first clinically available thiazolidinedione, was approved for use in patients who have failed diet therapy and, in combination with insulin and/or sulfonylureas, in patients inadequately controlled with these agents alone (117). Although studies have documented the hypoglycemic efficacy of troglitazone in patients with type 2 diabetes, its use was associated with elevated liver enzymes, liver damage, and death... 

A biopsy is often required to make a diagnosis of most types of liver disease. A specimen of liver can be used to identify fibrosis, cirrhosis, cholestasis and hepatitis, both acute and chronic, and tumours. Biochemical measurements can also be taken from a biopsy specimen to determine iron and copper content, virology, microbiology and haematology (e.g. increased numbers of eosinophils in a drug-induced cause). The biopsy can give an indication of the extent of the liver damage. See Chapter 3 for slides of liver biopsies. 

ALCOHOL KETOCONAZOLE May T risk of liver damage. Symptoms of nausea, headache, flushing and discomfort (similar to a disulfiram-type reaction) may occur Additive liver toxicity Be aware... 

Primary cells are typically cells from the liver, as these are the most easily obtained and the majority are the same type of cell, whereas those from most other organs are a mixture of types of cells. Primary liver cells are the most likely to be representative of the organ in the whole animal. These cells however, will indicate the effects (if any) that the chemical has only on the liver. They do not necessarily predict the effects on other organs or tissues. Furthermore, research has shown that the way in which isolated cells in the laboratory respond to chemicals is not always the same as the way they respond in the animal or human. They are often less sensitive, sometimes requiring a concentration of chemical many times higher than that which causes an effect in the live whole animal. For example, when isolated human liver cells are exposed to paracetamol, toxic effects are observed only if a concentration of paracetamol is used that is at least ten times higher than the level that causes liver damage in humans after an overdose. Unlike a cell in vitro, a cell in an animal is... 

Many chemicals that are acutely toxic are not chronically toxic, and vice versa. For example, pure vitamin D exhibits high acute toxicity. However, low repeated doses (such as in the normal intake of milk) are not only nontoxic but also essential to good health. For chemicals that are both acutely and chronically toxic, the mechanisms of the two types of toxicity are often different. For example, acute toxicity from a large dose of chloroform is caused by effects on the central nervous system that cause dizziness and narcosis. However, ingesting water containing trace concentrations of chloroform over a lifetime results in liver damage and cancer (Stewart, 1971). 

Regenerative lesions are the result of localized proliferation of liver cells and their stroma. They are regarded as the main response to various types of liver damage. 

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